Porous polymeric biomaterials and implants composed of biodegradable polymers have been presented in numerous papers and patents. These biomaterials and implants are generally made of aliphatic polyesters such as polylactic acids) and polylactides [PLAs], poly(glycolic acids) and polyglycolides [PGAs], poly(lactic-co-glycolic) and poly(lactide-co-glycolide) [PLGA], polyglyconate, poly(hydroxyalkanoates) [PHAs], polyorthoesters [POEs], polycaprolactones [PCLs], polydioxanone [PDS], polyanhydrides [PANs], and their copolymers. The American Food and Drug Administration (FDA) has cleared medical devices made from homopolymers or copolymers of glycolide, lactide, caprolactone, p-dioxanone and trimethylene carbonate.
Porous polymeric biomaterials have been promoted as carriers or scaffolds for repairing tissues, delivering drugs and bioactive compounds, encapsulating cells or bioengineering artificial tissues. The repair or regeneration of bone, cartilage, skin, liver, etc have attracted interest in such biodegradable porous polymer materials.
A number of physico-chemical techniques have been proposed to build such porous polymer structures. Washburn et al. (Co-extrusion of biocompatible polymers for scaffolds with co-continuous morphology, New York, John Wiley and Sons, Inc. 2002) disclose an approach using the melt blending of two immiscible polymers, only one of which being soluble in water (or another solvent) and at least the other one of which being biodegradable. Melt blending takes place in a twin screw extruder and is followed by selective extraction of one of the polymers to generate a porous biodegradable material, having a continuous network of void spaces. This material is then used to carry out tissue engineering.
Although this paper briefly mentions some factors that control the morphology of the extruded material, for example the viscosity of each polymer, the interfacial tension between the phases and the mixing conditions, it remains completely silent about how to closely control said morphology by manipulating such factors. In one sample obtained according to the Washburn et al. technique, the pore size can vary from 20 to 150 micron in diameter from one end to the other of the void network. There is definitely a lack of pore size uniformity or distribution control in the continuous void network.
Besides, other techniques have also been used, a few examples of which are cited below, with the alternate drawbacks of leading either to a non-continuous void space or to a non-controlled continuous void network. Moreover, most of the prior art leads to the development of articles with dimensions and shapes limited by the process (film, membrane, and disk).
Biodegradable Microporous Polymer Materials Obtained Using Solid Porogens
Solid porogens, soluble in water or specific solvents, were used to develop polymer foams made of PLAs, PGAs or PLGA for tissue engineering. This particulate-leaching method consists in dispersing solid particles in a polymer solution, followed by the selective extraction of the particles. U.S. Pat. No. 5,522,895 (Mikos) and U.S. Pat. No. 5,514,378 to Mikos et al. describe such an approach to prepare porous polymer membranes by dispersing particles (salts or an organic or inorganic compound, proteins, polysaccharides) in a biocompatible polymer solution, leaching the polymer solvent, dissolving the particles and removing the solvent by evaporation to form a porous membrane. Three-dimensional structures are achieved by laminating a number of various membranes.
Biodegradable Microporous Polymer Materials Obtained by Phase Separation from Polymer Solutions
Phase separation of polymer solutions was a straightforward porogen method for the production of polymer porous foams. This phase separation may be induced thermally (for example, by freeze-drying), by dry casting, by immersion precipitation, or by precipitation from the vapour phase. U.S. Pat. No. 5,102,983 (Kennedy) and U.S. Pat. No. 6,334,968 (Shapiro et al.) use a freeze-drying step. U.S. Pat. No. 5,866,155 (Laurencin et al.) provides methods for producing polymer microspheres using a dissolution/solvent evaporation technique. U.S. Pat. Nos. 5,716,413, 5,863,297, 6,203,573 (Walter, et al) and U.S. Pat. No. 5,607,474 (Athanasiou, et al) use precipitated polymer gel masses to produce a molded biodegradable, porous polymeric implant. U.S. Pat. No. 52,902,494 (Coombes et al.) and U.S. Pat. No. 5,492,697 (Boyan et al.) use gel casting. The gel is extracted with a non-solvent prior to drying, in order to obtain the microporous materials. U.S. Pat. Nos. 5,502,092 and 5,856,367 (Barrows et al.) use a polymer dissolved in a low molecular weight material or monomer, then remove the latter by leaching with a solvent which does not react undesirably with the polymer. U.S. Pat. Nos. 6,333,029, 6,355,699, 6,365,149 to Vyakarnam et al. describe the lyophilization process for forming biocompatible foam structures, by solidifying a solution of a solvent and a bioabsorbable polymer to form a solid, then subliming the solvent out of the solid.
U.S. Pat. No. 5,869,080 (McGregor et al.) uses a solution of polymer and adds particles of a second material (frozen water) and removes the solvent and the second material by freeze-drying to leave the porous implant material.
U.S. Pat. No. 5,686,091 (Leong, et al) discloses a method in which biodegradable porous polymer scaffolds are prepared by molding a solvent solution of the polymer under conditions permitting spinodal decomposition, followed by quenching of the polymer solution in the mold and sublimation of the solvent from the solution.
U.S. Pat. No. 5,723,508 (Healy et al.) discloses a method in which biodegradable porous polymer scaffolds are prepared by forming an emulsion of the polymer, a first solvent in which the polymer is soluble, and a second polymer that is immiscible with the first solvent, and then freeze-drying the emulsion under conditions that do not break the emulsion or throw the polymer out of solution.
U.S. Pat. Nos. 6,103,255 and 6,337,198 (Levene et al.) describe a method employing thermally induced phase separation to fabricate highly porous biodegradable materials. Depending upon the thermodynamics, the kinetics and the rate of cooling, phase separation will occur either by solvent crystallization or liquid-liquid demixing. This invention employs solvents and processing conditions under which solvent crystallization predominates as the phase separation mechanism to obtain a porous polymer scaffold with a bimodal pore diameter distribution.
U.S. Pat. No. 6,013,853 (Athanasiou et al.) relates to a method of making a biodegradable, porous, polymeric implant by a combination of dissolution/precipitation/drying and treatment with high vacuum.
Textile-Based Porous Materials
U.S. Pat. No. 4,186,448 (Brekke et al., 1980) describes the use of a porous meshwork of plugs composed of polyhydroxy acid polymers such as polylactide for healing bone voids. U.S. Pat. Nos. 5,755,792 and 5,133,755 (Brekke) present the use of vacuum foaming techniques and a process of forming connected spun filaments.
U.S. Pat. No. 6,245,345 (Swanbom et al.) describes a method to produce a filamentous porous mesh as biodegradable scaffold. U.S. Pat. No. 5,711,960 (Shikinami), U.S. Pat. Nos. 5,567,612 and 5,770,193 (Vacanti, et al), and U.S. Pat. No. 5,769,899 (Schwartz, et al) use a method to make biodegradable textile-based fibrous scaffolds.
Other Methods for Obtaining Biodegradable Microporous Materials
U.S. Pat. No. 6,281,256 (Harris et al.) describes the preparation of porous polymer materials by a combination of gas forming and particulate leaching steps. U.S. Pat. Nos. 5,677,355 and 5,969,020 (Shalaby et al.) use a polymer melt with a fugitive compound that sublimes at temperatures greater than room temperature or can be extracted, in order to produce microcellular foams.
None of the cited prior art documents disclose a precise control of the combined interconnectivity of the pores, void volume and pore size distribution. More specifically, the prior art fails to recognize the considerable effect of the use of a compatibilizer in a melt polymer blend for such purpose. The prior art also remains silent on any processing technique to prepare complex shapes of biodegradable, continuous, porous, polymer structures.
Thus remains a need for a technique allowing the control of the morphology, void volume and pore size distribution of the void volume in biodegradable porous articles.
Thus also remains a need for biodegradable articles having an essentially continuous porosity, controlled void volume and a unimodal pore size distribution set to a predefined unimodal peak location.
The present invention seeks to meet these and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.